Johnny Depp as Captain Jack Sparrow: Depp reprises his iconic role as the witty, cunning, and charismatic pirate Jack Sparrow, who embarks on a new adventure to find the legendary Fountain of Youth.
Penelope Cruz as Angelica Teach: Cruz portrays Angelica, a beautiful and dangerous pirate who crosses paths with Jack Sparrow. She is revealed to be the daughter of the notorious pirate Blackbeard.
Ian McShane as Blackbeard: McShane plays Captain Edward Teach, also known as Blackbeard, one of the most formidable and feared pirates of all time. He is the main antagonist of the film and seeks the Fountain of Youth to attain immortality.
Geoffrey Rush as Captain Hector Barbossa: Rush returns as Hector Barbossa, the former pirate captain turned privateer. He joins Jack Sparrow's quest for the Fountain of Youth, seeking redemption for his past misdeeds.
Kevin McNally as Joshamee Gibbs: McNally reprises his role as Joshamee Gibbs, Jack Sparrow's loyal first mate and confidant. He accompanies Sparrow on his journey to find the Fountain of Youth.
Sam Claflin as Philip Swift: Claflin portrays Philip Swift, a young missionary and cartographer who joins forces with Jack Sparrow. He is searching for the Fountain of Youth to cure his father's illness.
Àstrid Bergès-Frisbey as Syrena: Bergès-Frisbey plays Syrena, a mysterious mermaid who becomes entangled in Jack Sparrow's adventure. She possesses valuable knowledge about the Fountain of Youth.
Richard Griffiths as King George II: Griffiths appears as King George II of Great Britain, who sends a naval expedition led by Captain Hector Barbossa to find the Fountain of Youth before the Spanish can claim it.
In addition to these lead roles, the film features several other notable actors in supporting roles, including Judi Dench as the enigmatic voodoo priestess Madame Jollywood and Keith Richards, who makes a cameo appearance as Jack Sparrow's father, Captain Teague.